Sirtuin inhibition protects from the polyalanine muscular dystrophy protein PABPN1

Hum Mol Genet. 2008 Jul 15;17(14):2108-17. doi: 10.1093/hmg/ddn109. Epub 2008 Apr 7.

Abstract

Oculopharyngeal muscular dystrophy (OPMD) is caused by polyalanine expansion in nuclear protein PABPN1 [poly(A) binding protein nuclear 1] and characterized by muscle degeneration. Druggable modifiers of proteotoxicity in degenerative diseases, notably the longevity modulators sirtuins, may constitute useful therapeutic targets. However, the modifiers of mutant PABPN1 are unknown. Here, we report that longevity and cell metabolism modifiers modulate mutant PABPN1 toxicity in the muscle cell. Using PABPN1 nematodes that show muscle cell degeneration and abnormal motility, we found that increased dosage of the sirtuin and deacetylase sir-2.1/SIRT1 exacerbated muscle pathology, an effect dependent on the transcription factor daf-16/FoxO and fuel sensor aak-2/AMPK (AMP-activated protein kinase), while null mutants of sir-2.1, daf-16 and aak-2 were protective. Consistently, the Sir2 inhibitor sirtinol was protective, whereas the Sir2 and AMPK activator resveratrol was detrimental. Furthermore, rescue by sirtinol was dependent on daf-16 and not aak-2, whereas aggravation by resveratrol was dependent on aak-2 and not daf-16. Finally, the survival of mammalian cells expressing mutant PABPN1 was promoted by sirtinol and decreased by resveratrol. Altogether, our data identify Sir2 and AMPK inhibition as therapeutic strategies for muscle protection in OPMD, extending the value of druggable proteins in cell maintenance networks to polyalanine diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Acetylation
  • Animals
  • Animals, Genetically Modified
  • Benzamides / pharmacology
  • COS Cells
  • Caenorhabditis elegans / drug effects
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / antagonists & inhibitors
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Cell Survival
  • Chlorocebus aethiops
  • Forkhead Transcription Factors
  • Gene Expression Regulation
  • Genes, Reporter
  • Histones / metabolism
  • Humans
  • Multienzyme Complexes
  • Muscles / metabolism
  • Muscles / physiopathology
  • Muscular Dystrophy, Oculopharyngeal / metabolism
  • Muscular Dystrophy, Oculopharyngeal / physiopathology
  • Muscular Dystrophy, Oculopharyngeal / therapy*
  • Naphthols / pharmacology
  • Peptide Initiation Factors / genetics
  • Peptide Initiation Factors / metabolism*
  • Peptides / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Resveratrol
  • Sirtuins / antagonists & inhibitors
  • Sirtuins / genetics
  • Sirtuins / metabolism*
  • Sirtuins / pharmacology
  • Stilbenes / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Benzamides
  • Caenorhabditis elegans Proteins
  • Forkhead Transcription Factors
  • Histones
  • Multienzyme Complexes
  • Naphthols
  • PAIP1 protein, human
  • Peptide Initiation Factors
  • Peptides
  • RNA-Binding Proteins
  • Stilbenes
  • Transcription Factors
  • daf-16 protein, C elegans
  • sirtinol
  • polyalanine
  • Protein-Serine-Threonine Kinases
  • AAK-2 protein, C elegans
  • AMP-Activated Protein Kinases
  • SIR-2.1 protein, C elegans
  • Sirtuins
  • Resveratrol